Animal experiments are central to identify latent and persistent reservoirs and examine interactions between the virus and host that lead to CNS inflammation and neurodegeneration. Blood, CSF and/or tissues from infected macaques are used by each Project in the Program. The animal studies are designed to address the following questions: In what tissues and cells does latent virus persist in macaques treated with combination antiretroviral therapy (CART)? Does CART using drugs that do not cross the blood-brain barrier completely suppress virus replication in the CNS? Does CART suppress inflammatory responses or neurodegeneration in the CNS? The overall hypothesis for this program is that CART using drugs that effectively suppress virus replication in the peripheral blood but do not cross the blood-brain barrier is not sufficient to prevent the establishment of viral reservoirs in the CNS and peripheral tissues. Continued low-level virus replication will continue in tissues, particularly in the CNS, leading to virus spread and reseeding and amplification of the reservoirs. This will result in inflammation in the CNS with subsequent neurodegeneration. Macaques will be inoculated with SIV using our well-characterized accelerated, consistent SIV/macaque model in which over 90% of inoculated macaques develop encephalitis by 3 months p.i. Macaques will be treated with CART beginning at 3 days p.i. when virus has entered the brain but has not yet reached peak acute replication, or at 21 days p.i. when acute virus replication in the CNS has declined and animals have reached their viral "set point." Animals in which CART is initiated at 3 days p.i. will be euthanized at 10, 21 or 87 days p.i., times that correspond to peak acute virus replication, early asymptomatic infection, and terminal infection in untreated animals. Macaques in which CART is initiated at 21 days p.i. will be euthanized after 84 days of treatment. Additional animals in which CART was initiated at 3 or 21 days p.i. will be taken off antiretroviral therapy and the macaques will be monitored and euthanized when they develop AIDS and/or CNS disease to determine whether resurgence of virus replication in the CNS occurs from pre-existing virus and/or renewed entry of virus from the periphery. To the best of our knowledge, we are the first laboratory to examine latent and persistent CNS and peripheral viral reservoirs in the context of combination antiretroviral therapy.